Role of IL-17-secreting T cells in anti-viral immunity

描述：这项应用将评估T细胞分泌促炎细胞因子IL-17在病毒感染中的作用。产生IL-17的T细胞可能起到预防感染的作用，或者可能介导炎症和免疫病理。已知干扰素可促进Th1/Tc1细胞的发育，同时抑制产生IL-17的T细胞的形成。 将对牛痘病毒模型进行研究。假说是，痘苗病毒可能促进产生IL-17的T细胞，因为：(1)痘苗病毒驱动产生对产生IL-17的T细胞分化至关重要的细胞因子(IL-6、TGFbeta1、TNFpha)；以及(2)痘苗病毒编码免疫调节蛋白，阻断干扰素的作用(抑制产生产生IL-17的T细胞)。提出了两个具体目标： (1)确定哪些转录因子有助于产生IL-17的T细胞的分化和这些细胞产生特定的细胞因子。将来自信号转导和转录激活因子(STAT3)、STAT4或T-bet缺陷小鼠的细胞与不同细胞因子在培养中处理相结合。 (2)研究痘苗病毒感染小鼠体内产生IL-17的T细胞的功能，表现为产生IL-17的T细胞发育改变的缺陷小鼠，过继转移产生IL-17的T细胞的作用以及抗血清中和IL-17的作用。 这些研究可能有助于改进的痘苗病毒疫苗的开发，这种疫苗可能会调节产生IL-17的T细胞的形成，并减少天花疫苗造成的破坏性炎症。这些研究将确定产生IL-17的T细胞在病毒感染中的作用。

Description: This application will evaluate the role of T cell secreting the pro-inflammatory cytokine IL-17 in virus infections. The IL-17-producing T cells may function to protect from infection or may mediate inflammation and immunopathology. IFN is known to promote the development of Th1/Tc1 cells while it inhibits the formation of IL-17 producing T cells. The vaccinia virus model will be investigated. The hypothesis is that vaccinia virus may promote the generation of IL-17-producing T cells because: (1) vaccinia virus drives the production of cytokines important for the differentiation of IL-17-producing T cells (IL-6, TGFbeta1, TNFalpha); and (2) vaccinia virus encodes immunomodulatory proteins that block IFN action (which inhibits the generation of IL-17-producing T cells). Two specific aims are proposed: (1) Define the transcription factors that contribute to the differentiation of IL-17-producting T cells and the production of specific cytokines by these cells. Combination of cells from mice deficient in signal transducer and activator of transcription (STAT3), STAT4 or T-bet and the treatment in culture with different cytokines will be employed. (2) To investigate the function of IL-17-producing T cells in mice infected with vaccinia virus, characterizing deficient mice with altered development of IL-17-producing T cells, the effect of adoptive transfer of IL-17-producing cells and the neutralization of IL-17 with antiserum. These studies may help the development of improved vaccinia virus vaccines which may regulate the formation of IL-17-producing T cells and reduce the damaging inflammation caused by the smallpox vaccine. These investigations will define the role of IL-17-producing T cells in virus infections.